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same situation that HD in terms of pharmacotherapy to delay/arrest the
progression of neurodegeneration, substances that reduce excitotoxicity,
calcium influx, oxidative stress and/or inflammation being the only options
assayed to date (for review, see [154, 155]), although the results obtained so
far are not as promising as expected [155]. Since cannabinoid agonists share
many of the above properties (for review, see [4–6]), they have been proposed
as potentially useful neuroprotective substances also in PD, although the issue
has been explored only very recently. However, their hypokinetic profile is a
disadvantage in this case, because, despite their neuroprotectant activity in
long-term treatments, they acutely enhance rather than reduce motor symptoms
in this disease, as revealed by a few clinical studies [7, 156, 157]. This is
compatible with the observation of overactivity in the endocannabinoid transmission
in the basal ganglia in PD in both patients [158] and animal models
[14, 131, 158–160]. This explains the hypokinetic profile of this disease and
the recent proposal of CB 1 receptor antagonists to alleviate bradykinesia and
rigidity, in particular at later phases of PD when L-dopa therapy is less effective
(for review, see [7, 161]), although the first experiences in laboratory animals
have been controversial [131, 162]. There would be only one exception
for cannabinoid agonists to be used for symptom relief in PD; that is, patients
for whom tremor is the major symptom. CB 1 receptor agonists might be useful
to alleviate this symptom, due to the well-know inhibitory effect of
cannabinoid agonists on glutamate release from subthalamonigral neurons
[163], whose hyperactivity is responsible for tremor [117]. However, the only
small clinical study carried out to test the effects of cannabinoids on parkinsonian
tremor led to negative results [164].
Coming back to the question of neuroprotection by cannabinoids in PD,
recent preclinical studies carried out with ∆ 9 -THC have revealed that this compound
could be also neuroprotective in PD [64]. The administration of ∆ 9 -THC
reversed the impairment of dopaminergic transmission in the basal ganglia of
rats with hemiparkinsonism caused by the unilateral application of 6-hydroxydopamine
[64]. These effects did not occur in the contralateral structures,
thus indicating that the effects of ∆ 9 -THC were produced by reducing
dopaminergic cell death in the lesioned side rather than producing up-regulatory
effects in surviving neurons [64]. The quantification of tyrosine hydroxylase
mRNA levels in the substantia nigra of these animals corroborated this
finding [64]. However, the fact that the same neuroprotective effects were
elicited by CBD, another plant-derived cannabinoid with negligible affinity for
the CB 1 receptor, suggests that these neuroprotective effects could be CB 1
receptor-independent, based on the antioxidant properties of both
plant-derived cannabinoids [64]. This observation is similar to the results
reported by Hampson et al. [56], who compared the neuroprotective effects of
∆ 9 -THC and CBD in rat cortical neuron cultures exposed to toxic levels of glutamate.
This observation is particularly important in PD, a disease in which
oxidative stress, together with excitotoxicity and mitochondrial failure, is a
major hallmark in the pathogenesis of the disease [117].